The present application is the continuation of CA140043 for a new grant cycle. Progress made during the past four years defined new requirements of mitochondrial bioenergetics in tumor progression (Project 1), dissected the role of integrin-mediated cell adhesion in prostate cancer invasion (Project 2), and elucidated transcriptional circuitries of bone metastatic disease (Project 3). The original specific aims were met, collaborative publications appeared in the premiere peer-reviewed literature, and a goal of merging mechanisms of prostate cancer progression with credentialing new therapeutic candidates for advanced disease was fulfilled. As a whole, the Program had a multiplier effect for prostate cancer research, enabling additional federal and foundation funding, generation of new intellectual property, and expansion of educational venues. Building on these accomplishments, the present continuation application has now been extensively restructured. Brought back to a single physical location in Philadelphia with a rich environment for prostate cancer research, this continuation application stresses scientific innovation and focuses on emerging new paradigms of disease progression. The overarching goal is to understand new mechanisms of metastatic competency in prostate cancer, while identifying ?actionable? therapeutic targets for late-stage disease. Project 1 (Project Leader, Dr. Altieri) will study a novel pathway of spatiotemporal mitochondrial bioenergetics, which functions as a regional energy source to fuel membrane dynamics of cell motility and supports prostate cancer invasion. Project 2 (Project Leader, Dr. Languino) will focus on the role of prostate cancer-released exosomes as a new mechanism of intercellular communication that promotes integrin- regulated tumor cell motility. Project 3 (Project Leader, Dr. Gabrilovich) is a new addition to the Program, and will characterize the bioenergetics requirements of Myeloid-Derived Suppressor Cells (MDSC) in the establishment of immunosuppressive primary and pre-metastatic tumor sites during prostate cancer progression. An Administration and Biostatistics Core (Core A) will coordinate scientific integration among all Program components, provide state-of-the-art biostatistics support, enable access to clinically-annotated patient material, and ensure timely financial and administrative oversight. A new Mass Spectrometry Core (Core B) will support metabolomics profiling and quantitative proteomics of regulatory protein complexes, secretomes and proteomes pursued by the three Projects. Overall, the Program builds on a decades-long history of collaboration among its experienced investigators, a straightforward and cost-effective organizational layout that maximizes integration and reduces redundancies, and an intellectually-stimulating environment for collaborative prostate cancer research. The proposed studies are innovative, connecting themes of mitochondrial metabolism, exosome biology, and immunosuppressive checkpoints in a single signaling network not previously associated with prostate cancer or metastatic competency. The results have the potential to transform our understanding of advanced prostate cancer, and change clinical practice by identifying novel therapeutic targets for late-stage disease, still a major cause of morbidity and mortality in these patients.